The innate immune system has been considered as an ancient system and less important than the adaptive immune system. However, the interest in innate immunity has grown significantly in the past few years marked by the identification of Toll-like receptors, a member of pattern recognition receptors (PRRs). The PRRs are crucial for the identification of self- and non-self-antigen and play a role in the initiation of signaling events that activate the effective immune response. These sensor signals through interweaving signaling cascades which result in the production of interferons and cytokines as the effector of immune system. Ubiquitin and ubiquitin-like modifiers (UBLs) actively mediate the rapid and versatile regulatory processes that initiate the activation of the innate immune system cascade. The seven in absentia homolog (SIAH) is a potent RING finger E3 ubiquitin ligase that is known to involve in several stress responses, including hypoxia, oxidative stress, DNA damage stress, and inflammation. In this review, the role of SIAH will be discussed as an E3 ubiquitin ligase on the regulation of innate immune.

Keywords: E3 ligase, innate immunity, regulation, seven in absentia homolog.

1. Kawai, T. and Akira, S. (2007) Signaling to NF-?B by toll-like receptors. Trends Mol. Med., 13(11): 460-469. [Crossref] [PubMed]

2. Lawrence, T. (2009) The nuclear factor NF-?B pathway in inflammation. Cold Spring Harb. Perspect. Biol., 1(6): a001651-a001651. [Crossref] [PubMed] [PMC]

3. Liu, X., Wang, Q., Chen, W. and Wang, C. (2013) Dynamic regulation of innate immunity by ubiquitin and ubiquitin-like proteins. Cytokine Growth Factor Rev., 24(6): 559-570. [Crossref] [PubMed]

4. Groothuis, T.A., Dantuma, N.P., Neefjes, J. and Salomons, F.A. (2006) Ubiquitin crosstalk connecting cellular processes. Cell Div., 1(11): 21. [Crossref] [PubMed] [PMC]

5. Jiang, X. and Chen, Z.J. (2012) The role of ubiquitylation in immune defence and pathogen evasion. Nat. Rev. Immunol., 12(1): 35-48. [Crossref] [PubMed] [PMC]

6. Takeuchi, O. and Akira, S. (2010) Pattern recognition receptors and inflammation. Cell, 140(6): 805-820. [Crossref] [PubMed]

7. Li, J., Chai, Q.Y. and Liu, C.H. (2016) The ubiquitin system: A critical regulator of innate immunity and pathogen-host interactions. Cell Mol. Immunol., 13(5): 560-576. [Crossref] [PubMed] [PMC]

8. Qi, J., Kim, H., Scortegagna, M. and Ronai, Z.A. (2013) Regulators and effectors of Siah ubiquitin ligases. Cell Biochem. Biophys., 67(1): 15-24. [Crossref] [PubMed] [PMC]

9. Nakayama, K., Qi, J. and Ronai, Z. (2009) The ubiquitin ligase Siah2 and the hypoxia response. Mol. Cancer Res., 7(4): 443-451. [Crossref] [PubMed] [PMC]

10. Mo, C., Dai, Y., Kang, N., Cui, L. and He, W. (2012) Ectopic expression of human MutS homologue 2 on renal carcinoma cells is induced by oxidative stress with interleukin-18 promotion via p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) signaling pathways. J. Biol. Chem., 287(23): 19242-19254. [Crossref] [PubMed] [PMC]

11. Jing, Y., Liu, L.Z., Jiang, Y., Zhu, Y., Guo, N.L., Barnett, J., Rojanasakul, Y., Agani, F. and Jiang, B.H. (2012) Cadmium increases HIF-1 and VEGF expression through ROS, ERK, and AKT signaling pathways and induces malignant transformation of human bronchial epithelial cells. Toxicol. Sci., 125(1): 10-19. [Crossref] [PubMed] [PMC]

12. Jang, K.L., Shackelford, J., Seo, S.Y. and Pagano, J.S. (2005) Up-regulation of -catenin by a viral oncogene correlates with inhibition of the seven in absentia homolog 1 in B lymphoma cells. Proc. Natl. Acad. Sci., 102(51): 18431-18436. [Crossref] [PubMed] [PMC]

13. Habelhah, H., Frew, I.J., Laine, A., Janes, P.W., Relaix, F., Sassoon, D., Bowtell, D.D. and Ronai, Z. (2002) Stress-induced decrease in TRAF2 stability is mediated by Siah2. EMBO J., 21(21): 5756-5765. [Crossref] [PubMed] [PMC]

14. Streich, F.C. and Lima, C.D. (2014) Structural and functional insights to ubiquitin-like protein conjugation. Annu. Rev. Biophys., 43: 357-379. [Crossref] [PubMed] [PMC]

15. Callis, J. (2014) The ubiquitination machinery of the ubiquitin system. Arab. B., 12: e0174. [Crossref] [PubMed] [PMC]

16. Oudshoorn, D., Versteeg, G.A. and Kikkert, M (2012) Regulation of the innate immune system by ubiquitin and ubiquitin-like modifiers. Cytokine Growth Factor Rev., 23(6): 273-282. [Crossref] [PubMed]

17. Heaton, S.M., Borg, N.A. and Dixit, V.M. (2016) Ubiquitin in the activation and attenuation of innate antiviral immunity. J. Exp. Med., 213(1): 1-13. [Crossref] [PubMed] [PMC]

18. Zhao, B., Bhuripanyo, K., Schneider, J., Zhang, K., Schindelin, H., Boone, D. and Yin, J. (2012) Specificity of the E1-E2-E3 enzymatic cascade for ubiquitin C-terminal sequences identified by phage display. ACS Chem. Biol., 7(12): 2027-2035. [Crossref] [PubMed] [PMC]

19. Li, W., Bengtson, M.H., Ulbrich, A., Matsuda, A., Reddy, V.A., Orth, A., Chanda, S.K., Batalov, S. and Joazeiro, C.A. (2008) Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling. PLoS One, 3(1): e1487. [Crossref] [PubMed] [PMC]

20. Saeki, Y. (2017) Ubiquitin recognition by the proteasome. J. Biochem., 161(2): 113-124. [Crossref]

21. Dikic, I., Wakatsuki, S. and Walters, K.J. (2009) Ubiquitin-binding domains - From structures to functions. Nat. Rev. Mol. Cell Biol., 10(10): 659-671. [Crossref] [PubMed]

22. Behrends, C. and Harper, J.W. (2011) Constructing and decoding unconventional ubiquitin chains. Nat. Struct. Mol. Biol., 18(5): 520-528. [Crossref] [PubMed]

23. Komander, D. and Rape, M. (2012) The ubiquitin code. Annu. Rev. Biochem., 81(1): 203-229. [Crossref] [PubMed]

24. Kerscher, O., Felberbaum, R. and Hochstrasser, M. (2006) Modification of proteins by ubiquitin and ubiquitin-like proteins. Annu. Rev. Cell Dev. Biol., 22: 159-180. [Crossref] [PubMed]

25. Kulathu, Y. and Komander, D. (2012) Atypical ubiquitylation - The unexplored world of polyubiquitin beyond Lys48 and Lys63 linkages. Nat. Rev. Mol. Cell Biol., 13(8): 508-523. [Crossref] [PubMed]

26. Tokunaga, F., Sakata, S., Saeki, Y., Satomi, Y., Kirisako, T., Kamei, K., Nakagawa, T., Kato, M., Murata, S., Yamaoka, S., Yamamoto, M., Akira, S., Takao, T., Tanaka, K. and Iwai, K. (2009) Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation. Nat. Cell Biol., 11(2):123-132. [Crossref] [PubMed]

27. Xia, Z.P., Sun, L., Chen, X., Pineda, G., Jiang, X., Adhikari, A., Zeng, W. and Chen, Z.J. (2009) Direct activation of protein kinases by unanchored polyubiquitin chains. Nature, 461(7260): 114-119. [Crossref] [PubMed] [PMC]

28. Lee, M.J., Lee, B-H., Hanna, J., King, R.W. and Finley, D. (2011) Trimming of ubiquitin chains by proteasome-associated deubiquitinating enzymes. Mol. Cell Proteom., 10(5): R110.003871.

29. Eletr, Z.M. and Wilkinson, K.D. (2014) Regulation of proteolysis by human deubiquitinating enzymes. Biochim. Biophys. Acta - Mol. Cell Res., 1843(1): 114-128.

30. MacGurn, J.A., Hsu, P.C. and Emr, S.D. (2012) Ubiquitin and membrane protein turnover: From cradle to grave. Annu. Rev. Biochem., 81: 231-259. [Crossref] [PubMed]

31. Hu, H. and Sun, S.C. (2016) Ubiquitin signaling in immune responses. Cell Res., 26(4): 457-483. [Crossref] [PubMed] [PMC]

32. Turvey, S.E. and Broide, D.H. (2010) Innate immunity. J. Allergy Clin. Immunol., 125(2): S24-S32. [Crossref] [PubMed] [PMC]

33. Cusson-Hermance, N., Khurana, S., Lee, T.H., Fitzgerald, K.A. and Kelliher, M.A. (2005) Rip1 mediates the trif-dependent toll-like receptor 3- and 4-induced NF-{kappa}B activation but does not contribute to interferon regulatory factor 3 activation. J. Biol. Chem., 280(44): 36560-36566. [Crossref] [PubMed]

34. Loo, Y.M. and Gale, M. (2011) Immune signaling by RIG-I-like receptors. Immunity, 34(5): 680-692. [Crossref] [PubMed] [PMC]

35. Bogdan, S., Senkel, S., Esser, F., Ryffel, G.U. and Pogge v Strandmann, E. (2001) Misexpression of xsiah-2 induces a small eye phenotype in xenopus. Mech. Dev., 103(1-2): 61-69. [Crossref]

36. Carthew, R.W. and Rubin, G.M. (1990) Seven in absentia, a gene required for specification of R7 cell fate in the drosophila eye. Cell, 63(3): 561-577. [Crossref]

37. Della, N.G., Senior, P.V. and Bowtell, D.D. (1993) Isolation and characterisation of murine homologues of the drosophila seven in absentia gene (sina). Development, 117(4): 1333-1343. [PubMed]

38. Pepper, I.J., Van Sciver, R.E. and Tang, A.H. (2017) Phylogenetic analysis of the SINA/SIAH ubiquitin E3 ligase family in metazoa. BMC Evol. Biol., 17: 182. [Crossref] [PubMed] [PMC]

39. Robbins, C.M., Tembe, W.A., Baker, A., Sinari, S., Moses, T.Y., Beckstrom-Sternberg, S., Beckstrom-Sternberg, J., Barrett, M., Long, J., Chinnaiyan, A., Lowey, J., Suh, E., Pearson, J.V., Craig, D.W., Agus, D.B., Pienta, K.J. and Carpten, J.D. (2011) Copy number and targeted mutational analysis reveals novel somatic events in metastatic prostate tumors. Genome. Res., 21(1): 47-55. [Crossref] [PubMed] [PMC]

40. Zhang, Q., Wang, Z., Hou, F., Harding, R., Huang, X., Dong, A., Walker, J.R. and Tong, Y. (2017) The substrate binding domains of human SIAH E3 ubiquitin ligases are now crystal clear. Biochim. Biophys. Acta - Gen. Subj., 1861(1): 3095-3105. [Crossref] [PubMed]

41. Leon, O. and Roth, M. (2000) Zinc fingers: DNA binding and protein-protein interactions. Biol. Res., 33(1): 21-30. [Crossref] [PubMed]

42. Polekhina, G., House, C.M., Traficante, N., Mackay, J.P., Relaix, F., Sassoon, D.A., Parker, M.W. and Bowtell, D.D. (2002) Siah ubiquitin ligase is structurally related to TRAF and modulates TNF-alpha signaling. Nat. Struct. Biol., 9(1): 68-75. [Crossref] [PubMed]

43. Santelli, E., Leone, M., Li, C., Fukushima, T., Preece, N.E., Olson, A.J., Ely, K.R., Reed, J.C., Pellecchia, M., Liddington, R.C. and Matsuzawa, S. (2005) Structural analysis of siah1-siah-interacting protein interactions and insights into the assembly of an E3 ligase multiprotein complex. J. Biol. Chem., 280(40): 34278-34287. [Crossref] [PubMed]

44. House, C.M., Hancock, N.C., Moller, A., Cromer, B.A., Fedorov, V., Bowtell, D.D., Parker, M.W. and Polekhina, G. (2006) Elucidation of the substrate binding site of siah ubiquitin ligase. Structure, 14(4): 695-701. [Crossref] [PubMed]

45. Topolska-Wos, A.M., Shell, S.M., Kilanczyk, E., Szczepanowski, R.H., Chazin, W.J. and Filipek, A. (2015) Dimerization and phosphatase activity of calcyclin-binding protein/Siah-1 interacting protein: The influence of oxidative stress. FASEB J., 29(5): 1711-1724. [Crossref] [PubMed] [PMC]

46. Moller, A., House, C.M., Wong, C.S.F., Scanlon, D.B., Liu, M.C., Ronai, Z. and Bowtell, D.D. (2009) Inhibition of siah ubiquitin ligase function. Oncogene, 28(2): 289-296. [Crossref] [PubMed] [PMC]

47. House, C.M., Moller, A. and Bowtell, D.D.L. (2009) Siah proteins: Novel drug targets in the ras and hypoxia pathways. Cancer Res., 69(23): 8835-8838. [Crossref] [PubMed]

48. Baba, K. and Miyazaki, T. (2017) Critical function of siah2 in tumorigenesis. AIMS Mol. Sci., 4(7): 415-423. [Crossref]

49. Siswanto, F.M., Oguro, A. and Imaoka, S. (2017) Chlorogenic acid modulates hypoxia response of Hep3B cells. Pers. Med. Universe., 6: 12-16. [Crossref]

50. House, C.M., Frew, I.J., Huang, H.L., Wiche, G., Traficante, N., Nice, E., Catimel, B. and Bowtell, D.D. (2003) A binding motif for siah ubiquitin ligase. Proc. Natl. Acad. Sci., 100(6): 3101-3106. [Crossref] [PubMed] [PMC]

51. Nakayama, K., Frew, I.J., Hagensen, M., Skals, M., Habelhah, H., Bhoumik, A., Kadoya, T., Erdjument-Bromage, H., Tempst, P., Frappell, P.B., Bowtell, D.D. and Ronai, Z. (2004) Siah2 regulates stability of prolyl-hydroxylases, controls HIF1alpha abundance, and modulates physiological responses to hypoxia. Cell, 117(7): 941-952. [Crossref] [PubMed]

52. Nakayama, K., Gazdoiu, S., Abraham, R., Pan, Z.Q. and Ronai, Z. (2007) Hypoxia-induced assembly of prolyl hydroxylase PHD3 into complexes: Implications for its activity and susceptibility for degradation by the E3 ligase Siah2. Biochem. J., 401(1): 217-226. [Crossref] [PubMed] [PMC]

53. Alper, S., Laws, R., Lackford, B., Boyd, W.A., Dunlap, P., Freedman, J.H. and Schwartz, D.A. (2008) Identification of innate immunity genes and pathways using a comparative genomics approach. Proc. Natl. Acad. Sci., 105(19): 7016-7021. [Crossref] [PubMed] [PMC]

54. Couillault, C., Pujol, N., Reboul, J., Sabatier, L., Guichou, J.F., Kohara, Y. and Ewbank, J.J. (2004) TLR-independent control of innate immunity in Caenorhabditis elegans by the TIR domain adaptor protein TIR-1, an ortholog of human SARM. Nat. Immunol., 5(5): 488-494. [Crossref] [PubMed]

55. Li, S., Armstrong, C.M., Bertin, N., Ge, H., Milstein, S., Boxem, M., Vidalain, P.O., Han, J.D., Chesneau, A., Hao, T., Goldberg, D.S., Li, N., Martinez, M., Rual, J.F., Lamesch, P., Xu, L., Tewari, M., Wong, S.L., Zhang, L.V., Berriz, G.F., Jacotot, L., Vaglio, P., Reboul, J., Hirozane-Kishikawa, T., Li, Q., Gabel, H.W., Elewa, A., Baumgartner, B., Rose, D.J., Yu, H., Bosak, S., Sequerra, R., Fraser, A., Mango, S.E., Saxton, W.M., Strome, S., Van Den Heuvel, S., Piano, F., Vandenhaute, J., Sardet, C., Gerstein, M., Doucette-Stamm, L., Gunsalus, K.C., Harper, J.W., Cusick, M.E., Roth, F.P., Hill, D.E. and Vidal, M. (2004) A map of the interactome network of the metazoan C. elegans. Science, 303(5657): 540-543. [Crossref] [PubMed] [PMC]

56. Wang, J., Huo, K., Ma, L., Tang, L., Li, D., Huang, X., Yuan, Y., Li, C., Wang, W., Guan, W., Chen, H., Jin, C., Wei, J., Zhang, W., Yang, Y., Liu, Q., Zhou, Y., Zhang, C., Wu, Z., Xu, W., Zhang, Y., Liu, T., Yu, D., Zhang, Y., Chen, L., Zhu, D., Zhong, X., Kang, L., Gan, X., Yu, X., Ma, Q., Yan, J., Zhou, L., Liu, Z., Zhu, Y., Zhou, T., He, F. and Yang, X. (2011) Toward an understanding of the protein interaction network of the human liver. Mol. Syst. Biol., 7(1): 536. [Crossref] [PubMed] [PMC]

57. van Wijk, S.J.L., de Vries, S.J., Kemmeren, P., Huang, A., Boelens, R., Bonvin, A.M., Timmers, H.T. (2009) A comprehensive framework of E2-RING E3 interactions of the human ubiquitin-proteasome system. Mol. Syst. Biol., 5(2): 295. [PubMed] [PMC]

58. Hackney, A.C. and Koltun, K.J. (2012) The immune system and overtraining in athletes: Clinical implications. Acta. Clin. Croat., 51(4): 633-641. [PubMed]

59. Gholamnezhad, Z., Boskabady, M.H., Hosseini, M., Sankian, M. and Khajavi, R.A. (2014) Evaluation of immune response after moderate and overtraining exercise in wistar rat. Iran. J. Basic Med. Sci., 17(1): 1-8. [PubMed] [PMC]

60. Terry, S., Buart, S. and Chouaib, S. (2017) Hypoxic stress-induced tumor and immune plasticity, suppression, and impact on tumor heterogeneity. Front. Immunol., 8(3): 1-5. [Crossref]

61. Ai, M., Budhani, P., Sheng, J., Balasubramanyam, S., Bartkowiak, T., Jaiswal, A.R., Ager, C.R., Haria, D.D. and Curran, M.A. (2015) Tumor hypoxia drives immune suppression and immunotherapy resistance. J. Immunother. Cancer, 3(2): P392. [Crossref] [PMC]

62. Jin, Y., Hu, Y., Han, D. and Wang, M (2011) Chronic heat stress weakened the innate immunity and increased the virulence of highly pathogenic avian influenza virus H5N1 in mice. J. Biomed. Biotechnol., 2011(4): 1-10. [Crossref] [PubMed] [PMC]

63. Elsheikha, H.M., El-Motayam, M.H., Abouel-Nour, M.F. and Morsy, A.T.A. (2009) Oxidative stress and immune-suppression in Toxoplasma gondii positive blood donors: Implications for safe blood transfusion. J. Egypt. Soc. Parasitol., 39(2): 421-428. [PubMed]

64. Arimilli, S., Schmidt, E., Damratoski, B.E. and Prasad, G.L. (2017) Role of oxidative stress in the suppression of immune responses in peripheral blood mononuclear cells exposed to combustible tobacco product preparation. Inflammation, 40(5): 1622-1630. [Crossref] [PubMed] [PMC]

---